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Synergistic Interactions of Various Doses of Diethylstilbestrol and X-Irradiation on Mammary Neoplasia in Female ACI Rats¹

Medical Department, Brookhaven National Laboratory, Upton, New York 11973

The intent of this study was to investigate the relationship between diethylstilbestrol (DES) dose and its synergistic interaction with X-irradiation for mammary carcinogenesis in ACI rats. In addition, the role of prolactin in this synergism was studied. Ten groups of approximately 25 female ACI rats, 84 to 91 days of age, were implanted s.c. with a compressed 20-mg pellet containing either 5, 1.67, 0.56, 0.19, or 0 mg of DES combined with cholesterol. Two days later, one group at each dose level was exposed (whole body) to 150 R of 250 kVp X-radiation. Plasma prolactin levels were determined by radioimmunoassay on samples taken at approximately 100-day intervals. The experiment was terminated 659 days after pellet implantation. Three basic types of mammary neoplasms were found: individual mammary adenocarcinoma (MAC); multiple mammary adenocarcinoma (MMAC) consisting of four or more MAC's within a single quadrant of breast tissue; and mammary fibroadenoma. Increasing the dose of DES (with or without irradiation) increased the number of rats with a MAC (incidence) and the number of MAC's per rat while also decreasing the mean time of appearance of all MAC's. MMAC's were found only in rats treated with the two highest doses of DES (with or without irradiation), and this response appeared to be DES dose dependent. Combining irradiation with DES treatment (except at the lowest DES dose) produced a synergistic increase in the MAC and MMAC incidence and the number of MAC's and MMAC's per rat and decreased the time of appearance of all MAC's. Rats receiving only X-irradiation had only a few late-appearing MAC's. No MAC's were seen in the cholesterol control group. Fibroadenomas were very late-occurring tumors, and their time of appearance did not appear to be DES dose dependent (with or without irradiation). Almost all the rats in the three highest-dose groups had pituitary tumors, while in all other groups only about one-half of the animals had these tumors. There appeared to be a definite relationship between the dose of DES and both the initiation and the degree of plasma prolactin elevation for all DES doses except the lowest. These data suggest that in female ACI rats, MAC induction by DES alone or by the synergistic interaction of DES and X-irradiation is highly DES dose dependent. This DES dose dependence appears to be mediated via an estrogenic stimulation of prolactin secretion, since the higher and the earlier that prolactin was elevated the greater were the MAC and MMAC responses.

¹ Research performed under Contract Y01-CP-30213, with the Biological Models Segment of the Carcinogenesis Program of the National Cancer Institute. Brookhaven National Laboratory is operated by Associated Universities, Inc., under contract to the United States Department of Energy, Contract DE-AC02-76CH00016.

² To whom requests for reprints should be addressed.

Received 4/11/80. Accepted 7/30/80.

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